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Off To a Great Start:
First Syntheses by Three Untenured Synthetic Organic Chemists
Andrew J. PhillipsAssistant Professor (2002)
University of Colorado BoulderPostdoctoral Research: Peter Wipf (Pittsburgh)PhD: University of Cantebery (New Zealand)
Joseph M. ReadyAssistant Professor (2003)
University of Texas Southwestern Medical CenterPostdoctoral Research: John L. Wood (Yale)
PhD: Eric N. Jacobsen (Harvard)
Mohammad MovassaghiAssistant Professor (2003)
MITPostdoctoral Research: Eric N. Jacobsen (Harvard)
PhD: Andrew Meyers (Harvard)
Enantioselective Total Synthesis of (+) and (-)-Nigellamine A2J. Am. Chem. Soc. 2006, 128, 7428-7429Bian, J.; VanWingerden, M.; Ready, J. M.
H3CO
CH3
O PhO
OH
O
O
O
N
N
Nigellamine A2
H3CO
CH3
O PhO
OH
O
O
O
N
NIntramolecular Pd cat
allylic alkylation
Nozaki-Hiyama-Kishicyclization
Shi Epoxidation
Review of dolabellane diterpenes: Rodriguez, A. D.; Gonzalez, E.; Ramirez, C. Tetrahedron 1998, 54, 11683
Isolated: From Nigella sativa (black cumin); Yoshikawa, M.; et al. Org. Lett. 2004, 6, 869
Biological Activity: Potent lipid metabolism-promoting activity
Development of Pd(π-allyl) Cyclization to Form Tetrasubstituted Olefins
H3CO
CH3
O PhO
OH
O
O
O
N
N
EtO2C
EtO2C
R CH3
CH3
OAcEtO2C
EtO2C
R CH3
CH3
PdH3C
CH3R
EtO2CEtO2C
H3CCH3
R
EtO2CEtO2C
EtO2C
EtO2C
CH3
CH3OAc
RO
R= H, MOM, TBS, Bn, CH2SCH3
Pd(OAc)2 (10 mol%)PPh3 (40 mol%), NaH
>90% conversion
NOT Observed
H3CCH3
CO2Et
CO2Et
RO
Initial Attempts
Reasoned that the problem was due to the electronics of the OR group
Pd
CO2Et
EtO2C
H3C CH3
Stabilized
PdRO
CO2Et
EtO2C
H3C CH3
Destabilized
Solution was to change from CH2OR to a vinyl group
Application of Pd(π-allyl) Cyclization to Nigellamine A2
O
O
2 steps
HO
O
CO2Et
EtO2C
H3C CH3H3C CH3
EtO2CCO2Et
OH3C CH3
O
H3C CH3
CO2Et
EtO2C
PdH3C CH3
PPh2
O
N
t-Bu
CH3MgBr1) TBSCl2) BuLi, ClC(O)i-Pr3) HF•py
O
H3C CH3
HO
OHH3C CH3
1) I2, PPh32) NaCH(CO2Et)237% from lactone
LHMDS, S-LigandPd2(dba)3 (1.25 mol%)
100% conversion, 95 %ee
Ligand
Phosphinooxazoline Ligand: Dawson, G. J.; Frost, C. G.; Williams, J. M. J.; Coote, S. J. Tetrahedron Lett. 1993, 34, 3149
H
Elaboration of Cyclopenane Core
H3C CH3
EtO2CCO2Et
H
O
O
H3C CH3
I
CO2Et
HH
O
O
H3C CH3
CO2Et
HHI210:1 dr
63% over 2 steps
1) hv, (Bu3Sn)22) Bu4NF66% over 2 steps
TIPS SO2CF3
O
O
H3C CH3
I
CO2Et
HH
O
O
H3C CH3
CO2Et
HH
TIPS SO2CF3
O
O
H2C CH3
CO2Et
HHF3CO2S
TIPS
O
O
H3C CH3
CO2Et
HHTIPS SO2
CF3
Proposed Mechansim for Radical Alkynylation
Bu3Sn
Radical Alkynylation: Xiang, J.; Fuchs, P. L. Tetrahedron Lett. 1998, 39, 8597.
Water-Accelerated Methyliodination of Alkyne
O
OH
H3C CH3
HH
OH
O
O
H3C CH3
HH
I
OSi
t-Bu t-Bu
1) DIBAL-H2) NaBH4
1) Cp2Zr2Cl2, AlMe3, H2O (1:3:1); I22) (t-Bu)2Si(OTf)246% over 4 steps(27% recovered prior to methyliodination)
O
O
H3C CH3
CO2Et
HH
Zr[Cp2ZrCl2] H2O
T < 0 °CMe3Al
T> 0 °C
fastslow
MeAl
Cl
Me
MeZr
MeAl
O
Me
Me
R H
R H
Me AlMe2
Me3Al
Proposed Rationale for Water Acceleration
MeAl
OAl
Me
Me Me
no rateacceleration
Water Accelerated Methyliodination: Wipf, P; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068
Completion of the Synthesis of ent-Nigellamine A2
O
OH
H3C CH3
HHH3C
OH
CH3
I
O
H3C CH3
HHH3C
CH3
O OH
H3C CH3H3C
CH3
OH O Ph
O
HOH
1) PdCl2(dppf) (cat) 2) Bu4NF3) Cp2ZrCl2, Al3Me, H2O; I263% over 3 steps
TMSZnBr
H3CO
CH3
O PhO
OH
O
O
O
N
N
O
O
H3C CH3
HH
I
OSi
t-Bu t-Bu
ent- Nigellamine A2
1) PCC (50%)2) CrCl2, Ni(acac)2 (cat) sonication73% yield, d.r. >10:1
1) Dess Martin 2) LiAlH(i-Bu)2t-Bu82% over 2 steps
O
H3C CH3
HHH3C
CH3
O OH
H
1) LiAlH42) PhCOCl51% over 2 steps
1) Shi catalyst, oxone (7:1 chemoselectivity)2) Nicotinic acid, DCC, DMAP51% over 2 steps
O
O O
O
O
H3C
H3CO
H3C CH3Shi Catalyst
25 linear steps 0.6% yield
Shi Epoxidation: Shi, Y. Acc. Chem. Res. 2004, 37, 488; Wang, Z. -X.; Shi, Y. J. Org. Chem. 1998, 63, 3099.LiAlH(iBu)2tBu: Trost, B. M.; Nichimura, Y.; Yammamoto, K.; McElvain, S. S. J. Am. Chem. Soc. 1979, 101, 1328.
Total Synthesis of (+)-Cyanthiwigin UJ. Am. Chem. Soc. 2005, 127, 5334.
Pfeiffer, M. W. B.; Phillips, A. J.
OH
HOH
(+)-Cyanthiwigin U
Isolated: Jamaican sponge Myrmedioderma styx; Hamann, M. T. et al Tetrahedron, 2002, 58, 7809
No biological activity (but many structurally related compounds are active against various cancer cell line,as well as viruses such as HIV-1 and hepatitis B)
Retrosynthetic Analysis of Cyanthiwigin U
O
O
HH
HO
O
OOPiv
Xc
Xc= Chiral Auxiliary
OH
HOH
Diels-AlderCyclization
Two-directionaltandem ROM-RCM
Synthesis of ROM/RCM Precursor
O
OH OPiv
N N MesMes
Ru
PCy3PhCl
Cl
(5 mol%)93 % yield
O
OHOPiv
HO2CH
1) 1,4-dimethylcyclohexadiene TfOH, -78 oC (70%)2) CAN, CH3CN (aq), (82%)
1) LiAlH4, THF (99%)2) (COCl)2, DMSO, Et3N, (84%)
HH
1) , CeCl32) Dess-Martin Periodinane
MgBrH
PivO
O
O
H
O
O
Palomo Chiral Auxiliary: Palomo, C.; Oiarbide, M.; Garcia, J. M.; Gonzalez, A.; Lecumberri, A.; Linden, A. J. Am. Chem. Soc. 2002, 124, 10288
ROM/RCM to Form Desired Tricycle
N N MesMes
Ru
PCy3PhCl
Cl O
O
HHH
O
O
RuLnO
OHH
RuLn
O
OHH
HO
O
O
O
HH
ring openingmetathesis and/or
LnRu
OO
O
O
HH
RuLn
ring closingmetathesis
Previous work by Phillips: Minger, T. L.; Phillips, A. J. Tetrahedron Lett. 2002, 43, 5357.First example of ROM-RCM stradegy in total synthesis: Stille, J. R.; Grubbs, R. H. J. Am. Chem. Soc. 1986, 108, 855.
Completion of the Total Synthesis of Cyanthiwigin U
O
O
HHOHH
HO
H
HHHO
H
OH
HH O
O
HH OHO
H3C
LiAlH4, 92%(dr= 10:1)
i-PrLi, CeCl3
PCC, CH2Cl2 90% (over 2 steps)
MeLiquant. (dr= 9:1)
Cyanthiwigin U12 steps from Piv-ester
17% overall yield
Dauben oxidation: Dauben, W. G.; Michno, D. M. J. Org. Chem. 1977, 42, 682.
Total Synthesis and Absolute Stereochemical Assignmentof (+) and (-)-Galbulimia Alkaloid 13J. Am. Chem. Soc. 2006, 128, 8126.
Movassaghi, M.; Hunt, D. K.; Tjandra, M.
Isolated from the bark of Galbulimima belgraveana: Taylor, W. C. et al. Aust. J. Chem. 1967, 20, 1705Biological Activity: Galbulimima Alkaloid 13 has not been tested but Himacine is a potential treatment for Alzheimer's disease McKinney, M. et al. Bioorg. Med. Chem. Lett. 1992, 2, 797; 1995, 5, 61.Previous synthesis of (+/-) Galbulimima Alkaloid 13: Mander, L. N.; McLachlan, M. M. J. Am. Chem. Soc. 2003, 125, 2400.
Retrosynthetic Analysis of Galbulimima Alkaloid 13
Synthesis of Diels Alder Precursor
Br
Br
Me B(OH)2
OTBS
Me
TBSOBr
Me
TBSON
OO
TBSON
OO
TBSON
OO
OHC
Pd(PPh3)4, Tl2CO3, THF, H2O 23 °C
75 %
CuI, K2CO3, oxazolidin-2-one,(MeNHCH2)2, toluene, 110 °C
95%
1) TBAF, THF (95%)2) MnO2, CH2Cl2 (92%)3) TBSOTf, Et3N, CH2Cl2, -78 °C (93%)
Grubb's cat (2nd gen)acrolein, CH2Cl2, 23 °C
85%
Use of Tl2CO3: Hoshino, Y.; Miyaura, N.; Suzuki, A. Bull. Chem. Soc. Jpn. 1988, 61, 3008.Copper Catalyzed amidation: Jiang, L.; Fob, G. E.; Klapars, A.; Buchwald, S. Org Lett. 2003, 5, 3667.
Synthesis of Radical Cyclization Precursor
N
TBSO
O
HOHC
H
O
H
N
Me
HMeCl
toluene, 90 °C82% (>20:1 endo)TBSO
N
OO
OHC
racemic mixture
BuLi, THF -78 °C 85%
Ph2S(OC(Ph)(CF3)2)2, Ph-H81%
N
N
TBSO
H
O
O
H
H
N
N
TBSO
H
O
O
H
H
OH
N
N
TBSO
H
O
O
H
H
(equal mixture of two diastereomers)
Martin sulfurane: Martin, J. C.; Arhart, R. J. J. Am. Chem. Soc. 1971, 93, 4327.
Cyclizations to form Galbulimima Alkaloid 13 Core
(product of diastereomer not shown)
N
N
TBSO
H
O
O
H
H
1) NBS, NaHCO3, THF 0 °C2) Bu3SnH, AIBN Ph-H, 60 °C 55% yield
1) Et3N•(HF)3, THF2) NaBH4, EtOH, 0 °C 70% yield
(+ diastereomer)
First example of vinyl radical cyclizations: Stork, G.; Baine, N. H. J. Am. Chem. Soc. 1982, 104, 2321.
Completion of the Total Synthesis of Glabulimima Alkaloid 13
ClCO2Bn, Na2CO3, H2O, CH2Cl2
65%
IBX, TsOH•H2O, Ph-H, DMSO, 65 °C
80%
1) TMSI, CH2Cl2, 0 °C2) HCl (aq)3) NaOH (aq) 89%
20 linear steps3% overall yield